SMGr up Mini Review SM Journal of Background and Progress Isam Karam¹*, Ya Jun Yang² and Jian Yong Li² Cardiology and ¹Central Laboratory of Veterinary Research, Soba (Animal Resources Research Corporation ARRC) Sudan, ²Key Lab of New Animal Drug Project of Gansu Province; ; Key Lab of Veterinary Pharmaceutical Development, Ministry of Agriculture; Lanzhou Institute of Husbandry and Pharmaceutical Science of CAAS, Cardiovascular China Diseases Abstract

Hyperlipidemia is disorder disease characterize by an excess on blood which include , , low density and decrease in high density lipoprotein in blood stream. Hyperlipidemia is modifiable risk factor of and other cardiovascular disease; hyperlipidemia may be primary or secondary type according to the cause of hyperlipidemia either high food intake rich of fat or as result of other disease or metabolic disturbances. Hyperlipidemia may affect different animals, diagnostic by laboratory Article Information measure of blood indexes and the treatment of hyperlipidemia depend on reducing lipids on the blood stream. Received date: Jul 28, 2017 Accepted date: Aug 22, 2017 Introduction Published date: Aug 31, 2017 Hyperlipidemia which is a modifiable risk factor for atherosclerosis and related cardiovascular *Corresponding author diseases, including coronary heart disease, cerebral stroke, myocardial infarction and renal failure Isam Karam, Central Laboratory of are becoming a major health problem in the world recently [1]. Hyperlipidemia is a heterogeneous Veterinary Research, Soba (Animal group of disorders characterized by an excess of lipids in the blood stream, these lipids include Resources Research Corporation cholesterol, cholesterol esters, phospholipids, and . ARRC), Sudan, Tel: 00249912624503; Jacobson reported that hyperlipidemia refers to elevated levels of lipids and cholesterol in Email: [email protected] the blood and it is also identified as [2], to describe the manifestations of different disorders of lipoprotein metabolism. The term hyperlipidemia refers to increased concentrations Distributed under Creative Commons of lipids (triglycerides, cholesterol, or both) in the blood stream, increased blood concentrations CC-BY 4.0 of triglycerides referred to as , while increased blood concentrations of Keywords Hyperlipidemia; blood lipids; cholesterol are referred to as [1,3-5]. Another related condition, dyslipidemia cholesterol; lipoprotein indicates disorders of lipoprotein metabolism, including lipoprotein overproduction or deficiency. These disorders may manifest with the elevation of serum total cholesterol, Low-Density Lipoprotein (LDL), triglyceride concentrations, and a decrease in the High Density Lipoprotein (HDL) concentration. The main aim of treatment hyperlipidemia is to reduce the risk of developing ischemic heart disease, cardiovascular and cerebrovascular disease. The major lipids reported to be present in the plasma are fatty acids, triglycerides, cholesterol, cholesterol esters (compounds), and phospholipids. Lipids are transported in the blood as large . Other lipid soluble substances, present in much smaller amounts but of considerable physiological importance, include steroid hormones and fat-soluble vitamins. Four main classes of lipids can be recognized from a metabolic stand point. These are free fatty acids, triacylglycerol, phospholipids, and cholesterol and its esters [6]. The principle functions of lipids are to act as energy stores and to serve as important structural component of cells. To fulfill these functions, lipids have to be transported in plasma from one tissue to another, from the intestine or the to other tissues such as muscular or adipose tissue, or from the other tissues to the liver [7,8]. There are many groups of lipids three are most important from a clinical perspective: fatty acids, sterols (mainly cholesterol), and acylglycerols (mainly triglycerides) [9,10]. Fatty acids are relatively simple lipids and are also important components of many other lipids [9,10]. Lipids is water insoluble organic compounds, which are essential for many normal functions of living organisms: they are important components of cell membranes, they are used to store energy [11], and they play a significant role as enzyme co-factors, hormones, and intracellular messengers [11]. Because lipids are water-insoluble molecules, they cannot be transported in aqueous solutions, such as plasma. For that reason, lipids are transported in plasma as macromolecular complexes known as lipoproteins [3,5,9-15]. Lipoproteins are spherical structures that consist of a hydrophobic core containing lipids (i.e. triglycerides and/or cholesterol esters), and an amphophilic (i.e. both hydrophobic and hydrophilic) outer layer of phospholipids, free cholesterol and proteins that form a protective envelope surrounding the lipid core [5,9,10,12,15].

How to cite this article Karam I, Yang YJ and Li JY. Hyperlipidemia Background and Progress. SM J Cardiolog and Cardiovasc Disord. 2017; 3(2): 1011s2. SMGr up Copyright  Karam I

The proteins that are part of the lipoproteins are knownas triglycerides. Dyslipidemia is the term that is used if lipid levels are apolipoproteins (or apoproteins) and play a significant role in lipid outside the normal range. High levels of LDL cholesterol (the so- transport and metabolism [5,9,10,14,]. Lipoproteins can contain one called “bad cholesterol”) greatly increase the risk for atherosclerosis or a variety of apolipoproteins, which regulate their metabolic in because LDL particles contribute to the formation of atherosclerotic several physiological functions of lipoproteins such as facilitation of plaques. Low HDL levels (“good cholesterol”) are an independent lipid transport, maintenance of structural integrity, and activation of risk factor, because reverse cholesterol transport works to prevent certain enzymes that play key roles in lipid metabolism [5,9,10,14]. plaque formation, or even cause regression of plaques once they have formed. HDL may also have anti-inflammatory properties that help Lipoproteins are particles that contain triglycerides, phospholipids reduce the risk of atherosclerosis. Fasting triglyceride levels are used and cholesterol and amphipathic proteins called apolipoproteins. to estimate the level of VLDL. High levels of triglycerides are also Lipoproteins can be differentiated on the basis of their density, but associated with an increased risk for atherosclerosis, although the also by the types of lipoproteins it contain. The degree of lipid in mechanism is not entirely clear. a lipoprotein affects its density the lower density of a lipoprotein contains more lipids relative to protein. Plasma lipoproteins differ in Cholesterol is the main sterol in animal tissues, the major their physical and chemical characteristics such as size, density and source of cholesterol is dietary intake, but it can also be synthesized composition [11]. endogenously by the liver and other tissues. Cholesterol is absorbed from the intestine and transported to the liver by chylomicron The four major types of lipoproteins are chylomicrons, Very remnants. Hepatic cholesterol enters into the circulation as very low Low-Density Lipoprotein (VLDL), Low-Density Lipoprotein (LDL), density lipoprotein VLDL which is metabolized by lipoprotein lipase and High-Density Lipoprotein (HDL). Two types of lipoproteins enzyme to intermediate lipoprotein LDL and low density lipoprotein are triglyceride-rich: the chylomicrons and VLDL. Chylomicrons LDL which are then removed by liver or peripheral tissues. It plays are synthesized by enterocytes from lipids absorbed in the small a fundamental role in central metabolic pathways, such as bile acid intestine. VLDL is synthesized in the liver. The function of these metabolism and steroid hormone and vitamin D synthesis [9,10]. In lipoproteins is to deliver energy-rich triglycerides to cells in the the peripheral tissues cholesterol is converted to steroid hormones or body [11]. TG is stripped from chylomicrons and VLDL through the used to form the cell walls and membranes. The quantity of cholesterol action of lipoprotein lipase, an enzyme that is found on the surface transported from the liver to peripheral tissues greatly exceeds its of endothelial cells. This enzyme digests the TG to fatty acids and catabolism. So the excess amount of cholesterol is returned back glycerides, which can then diffuse into the cell to be oxidized, or in the to the liver by high density lipoprotein HDL. High cholesterol diet case of an adipose cell, to be re-synthesized into TG and stored in the leading to hyperlipidemia is regarded as an important factor in the cell. LDL delivers cholesterol to cells in the body. As VLDL particles development of Ischemic heart disease and the focus so far has been are stripped of triacylglycerol, they become denser. These particles are mainly on the systemic and coronary vascular effects of cholesterol. remodeled at the liver and transformed into LDL. The function of Although only few studies questioned the effect of cholesterol diet LDL is to deliver cholesterol to cells, where it is used in membranes, on the heart, several structural and functional alterations have or for the synthesis of steroid hormones [11]. been shown, suggesting that the endogenous adaptive mechanisms against myocardial stress are impaired. Thus, it is not surprising Cells take up cholesterol by receptor-mediated endocytosis. LDL that cholesterol is the most “decorated” molecule in history, having binds to a specific LDL receptor and is internalized in an endocytic contributed to as many as 13 Nobel prizes [16]. vesicle. Receptors are recycled to the cell surface, while hydrolysis in an endolysosome releases cholesterol for use in the cell. HDL Consequently, the principal steps in the absorption of dietary is involved in reverse cholesterol transport. Excess cholesterol is cholesterol are emulsification, hydrolysis of the ester bond bya eliminated from the body via the liver, which secretes cholesterol pancreatic esterase, micellar solubilization, and absorption in the in bile or converts it to bile salts. The liver removes LDL and other proximal jejunum reduction of cholesterol absorption by inhibiting lipoproteins from the circulation by receptor-mediated endocytosis. cholesterol micellization in the intestinal lumen is a new target site Additionally, excess cholesterol from cells is brought back to the liver of intervention for the treatment of hyperlipidemia. Moreover, it by HDL in a process known as reverse cholesterol transport [11]. enhances the incorporation of cholesterol into the mixed micelle HDL (or really, the HDL precursor) is synthesized and secreted by the and aids transport of free cholesterol to the enterocyte. Inhibition liver and small intestine. It travels in the circulation where it gathers of cholesterol esterase is expected to limit the absorption of dietary cholesterol to form mature HDL, which then returns the cholesterol cholesterol, resulting in delayed cholesterol absorption. In addition, to the liver via various pathways. binding bile acids by forming insoluble complexes in the intestine and increasing their fecal excretion have been hypothesized as a possible The link between cholesterol and heart disease was recognized mechanism of lowering plasma cholesterol level. This consequently through the study of individuals with familial hypercholesterolemia. reduces the bile acid pool. As a result, greater amount of cholesterol Individuals with this disorder have several-fold higher levels of is converted to bile acids to maintain a steady level in the circulation. circulating LDL due to a defect in the function of their LDL receptors. The continuous ingestion of high amounts of fat seems to be directly Without functioning LDL receptors, LDL is not cleared from related to hyperlipidemia in humans. Consequently, it has been the circulation. As well, because cholesterol cannot get into cells tried to provoke hyperlipidemia in laboratory animals, in order to efficiently, there is no negative feedback suppression of cholesterol understand better the relationship between disorders in cholesterol synthesis in the liver [11]. A lipid profile typically measures the metabolism and atherogenesis and to test possible treatments for the levels of total cholesterol, LDL cholesterol, HDL cholesterol, and reduction of circulating cholesterol level.

Citation: Karam I, Yang YJ and Li JY. Hyperlipidemia Background and Progress. SM J Cardiolog and Cardiovasc Disord. 2017; 3(2): 1011s2. Page 2/8 SMGr up Copyright  Karam I

Triglycerides are the most common and efficient form of stored in humans [23]. The mechanism by which hypertriglyceridemia energy in mammal. They can be derived from both dietary sources induces pancreatitis is not clear, but it has been suggested that and endogenous (hepatic) production [9,10]. It is worth noting that serum triglycerides are hydrolyzed by the action of pancreatic lipase, free fatty acids are transported bound to albumin and do not require leading to excessive production of free fatty acids, which are toxic to incorporation into lipoproteins for transport [3,5,9,10,13,14]. Plasma the pancreas [26,27]. However, recent large-scale cohort research in lipoproteins differ in their physical and chemical characteristics such USA and EU countries showed that there is no correlation between as size, density, and composition. CHD incidence and the values of TG and LDL except people with The Risk of Hyperlipidemia familial hypercholesterolemia [28]. According to the reports, USA Government has abolished the upper limit of intake of cholesterol per Hyperlipidemia is a condition characterized by increased day in 2015. Some of other countries made similar notification [29]. concentration of lipids (fats) in the bloodstream. Hyperlipidemia is one of the important factors associated with atherosclerosis, others Cause and Type of Hyperlipidemia being , smoking in human, diabetes mellitus, and other Dietary intake may not be the major source of cholesterol, of factors. Hyperlipidemia, atherosclerosis and related cardiovascular which 80% is synthesized in the body. It may be true that dietary intake diseases are becoming a major health problem in the world recently affects the amount of total cholesterol somewhat [30], but it can also even in companion animal clinic [17]. Hyperlipidemia has been be synthesized endogenously by the liver and other tissues. Several thought to be a modifiable risk of cardiovascular disease, a most diseases have been reported to cause hyperlipidemia. Endocrine common cause of mortality worldwide, accounting for almost 17 disease most commonly, canine hyperlipidemia is the result of an million deaths annually [18]. endocrine disorder, such as , diabetes mellitus, Hyperlipidemia is a major risk factor for “Atherosclerosis” or hyperadrenocorticism [5,11,13,14,31-33]. Hyperlipidemia can leading to heart attack and hypercholesterolemia nevertheless can also be the result of an inherited disease in certain breeds of dogs. impart some degree of risk for “Ischemic Heart Disease” (IHD). Hyperlipidemia in dogs and cats can be physiological (postprandial) Atherosclerosis and coronary heart disease are associated with or pathological. Pathological hyperlipidemia can result from increased elevated levels of Low Density Lipoprotein (LDL cholesterol) and lipoprotein synthesis or mobilization or decreased lipoprotein triacylglycerol with low levels of HDL cholesterol, consequent clearance. It can be primary (genetic or idiopathic) or secondary to cardiovascular and cerebrovascular disease. Increased circulating other disease processes. Hyperlipidemia Postprandial is physiological levels of Low Density Lipoprotein (LDL) underlie the development and transient, and typically resolves within 7-12 h after a meal, of atherosclerosis. Other complications are coronary heart disease, depending on the fat content of the meal [5,13,14,34]. For that reason, ischemic cerebrovascular disease, hypertension, and diabetes any determination of serum lipid concentrations should always mellitus (Type -II). follow a fast of at least 12 h. Veterinarians should be familiar with how to recognize and manage this clinical disorder. Protein Losing Low Density Lipoprotein (LDL) is pro-atherogenic. Hence high Nephropathy (PLN) Proteinuria associated with hyperlipidemia, levels of LDL increase “Coronary Heart Disease” (CHD) risk. High regardless of the cause, is often associated with hyperlipidemia in density lipoprotein (HDL) is anti-atherogenic. Hence low levels of dogs [11]. The most commonly reported lipid abnormality in dogs HDL also increases CHD risk. with PLN is hypercholesterolemia, which is usually mild or moderate Hyperlipidemia elevated LDL and Triglycerides (TG)-associated [35-39]. with increasing risk. Serum levels of HDL inversely related to risk. Hyperlipidemia can also result from a single inherited gene Hyperlipidemia is a major, modifiable risk factor for atherosclerosis defect in lipoprotein metabolic. Genetic defects in lipid metabolism; and cardiovascular disease, including coronary heart disease; monogenic familial hypercholesterolemia (homozygous or this is true both of disorders involving hypercholesterolemia and heterozygous) the defect may due to inactive LDL receptor, familial hypertriglyceridemia. Hyperlipidemia is a common risk factor for lipoprotein lipase deficiency the defect may due to inactive lipoprotein Cardiovascular Disease CVD, with 53.4 percent of adults in the lipase; familial combined hyperlipidemia the reason still unknown. United States having abnormal cholesterol values and 32 percent having elevated Low-Density Lipoprotein (LDL) cholesterol levels. There are two main types of hyperlipidemia: In the United States the (Am Fam Physician. 2011) mentioned that Primary Hyperlipidemia: This may occur due to high food intake Cardiovascular Disease (CVD) is the leading cause of mortality rich of fats and cholesterol or some of genetic defect and heredity accounting for 33.6 percent of all deaths in 2007 [19-21]. factor. Cardiovascular and related illnesses are one of the most common Secondary Hyperlipidemia: This occurs due to some diseases diseases prevalent in many parts of the world. An increased risk of or metabolic disturbances, e.g., diabetes mellitus, hypothyroidism, coronary heart diseases primarily associated with a high serum total obstructive liver disease, secondary causes of hyperlipidemia is the cholesterol, low density lipoprotein (LDL) concentration and a most common pathologic form of hyperlipidemia in dogs [11,40]. decrease in High Density Lipoprotein (HDL). Several diseases have been reported to cause hyperlipidemia. Today; severe hypertriglyceridemia is a known risk factor for Endocrine disease more commonly, canine hyperlipidemia is the pancreatitis in humans [22-25]. An increased risk for pancreatitis result of an endocrine disorder, such as hypothyroidism, diabetes from hyperlipidemia has been shown to exist when serum mellitus, or hyperadrenocorticism [5,13,14,31-33,41]. Increases in triglyceride concentrations exceed 11.3 mmol/L (1000 mg/dL. both serum triglyceride and cholesterol concentrations have been Hypercholesterolemia does not constitute a risk factor for pancreatitis reported in dogs with hypothyroidism [11,31,42-45]. In one study,

Citation: Karam I, Yang YJ and Li JY. Hyperlipidemia Background and Progress. SM J Cardiolog and Cardiovasc Disord. 2017; 3(2): 1011s2. Page 3/8 SMGr up Copyright  Karam I hypertriglyceridemia and hypercholesterolemia were found in 88% beds, which in turn leads to hydrolysis of VLDL triglycerides and and 78% of dogs with hypothyroidism, respectively [44]. Usually, the production of free fatty acids and glycerol. The VLDL molecules lipid abnormalities resolve after treatment of hypothyroidism [31]. remaining after hydrolysis of VLDL triglycerides (VLDL remnants) In dogs with diabetes mellitus, hyperlipidemia is most commonly are either removed from the circulation by the liver or undergo associated with hypertriglyceridemia but hypercholesterolemia might further transformation by lipoprotein lipase and/or hepatic lipase to also be present [5,13,31,41,42,45].Similarly, hypertriglyceridemia form LDL [5,9,10,14,15,52]. LDL which contains mainly cholesteryl usually resolves after successful treatment of diabetes but esters and phospholipids, circulates in the blood and binds to specific hypercholesterolemia might persist despite therapy [13,46]. The receptors that are widely distributed throughout tissues in order to presence of hyperlipidemia (hypertriglyceridemia and, to a lesser deliver cholesterol, which can be used for the synthesis of steroid degree, hypercholesterolemia) has long been associated with naturally hormones and cell membranes as well as for hepatic metabolism occurring pancreatitis in dogs [5,13,14,31,32,47-50]. However, it [9,10,15,]. HDLs have a critical role in the reverse cholesterol remains uncertain whether hyperlipidemia develops as a result of transport pathway; it is well known that a new attempt to reduce the pancreatitis or can be the cause of pancreatitis in some cases [13,51]. absorption of free fatty acids is by delaying triglyceride digestion with the inhibition of pancreatic lipase. Pancreatic cholesterol esterase Lipid Metabolism plays a pivotal role in hydrolyzing dietary cholesterol esters. The Lipid metabolism can be divided into two basic pathways: the hydrolysis of cholesterol esters in the lumen of the small intestine exogenous pathway, which is associated with the metabolism of is catalyzed by pancreatic cholesterol esterase, which liberates free exogenous (dietary) lipids Figure 1, and the endogenous pathway, cholesterol (Figure 1). which is associated with the metabolism of endogenously produced Hyperlipidemia in Different Animals lipids [9,10,14]. Hyperlipidemia can be the result of an inherited disease in Exogenous pathway the first step in dietary lipid metabolism some animals. Hyperlipidemia in dogs and cats can be physiological is digestion. Dietary lipids that reach the intestine duodenum then (postprandial) or pathological. Increased serum triglyceride and/or undergo emulsification, then hydrolyzed by the pancreatic and cholesterol concentrations have been observed in obese dogs [53- intestinal lipases [11,15]. Hydrolysis products (mainly free fatty acids 55]. The most profound changes were associated with severe chronic and monoglycerides) are then transferred to the intestinal epithelial obesity [55]. Weight loss in obese dogs leads to significant decreases cell, where they diffuse through the epithelial cell membranes into in both serum triglyceride and cholesterol concentrations [55,56]. the intestinal mucosal cells [11,15]. In the intestinal mucosal cell, free fatty acids and monoglycerides reassemble to form triglycerides, In pets, hyperlipidemia most often occurs as a consequence of which then combine with phospholipids, free and esterified some other disorder, such as diabetes mellitus (sugar diabetes), cholesterol [9,10,14,15,52]. Chylomicrons are the lipoprotein class hypothyroidism (low levels of circulating thyroid hormones), responsible for transfer of dietary lipids. After formation in the Cushing’s disease (excessively high cortisone levels in the body), enterocytes, chylomicrons, which mainly contain triglycerides, are certain liver diseases, and protein-losing nephropathy (a disease secreted into the lacteals and enter first the lymphatic and later the of the kidneys resulting in protein loss in the urine). However, blood circulation [9,10,14,15,52]. Lipoprotein which is exposed on hyperlipidemia can also occur spontaneously after a meal of high-fat the chylomicron surface, activates the lipoprotein lipase attached foods, particularly table scraps. to the capillary beds in adipose and skeletal muscle tissues, which After eating a meal, the nutrients in an animal’s body pass into the then hydrolyzes triglycerides into free fatty acids and glycerol small intestine, from which chylomicrons, micro particles of liquid [9,10,14,15,52]. Free fatty acids enters into the muscle cells (where fat, are absorbed 30-60 minutes later. Chylomicrons are in the classes they are used for energy production) and/or adipocytes (where they are re-esterified into triglycerides for storage). The cholesterol-rich remaining particles (chylomicron remnants), return to HDL and are recognized by specific hepatic receptors that rapidly remove them from the circulation by endocytosis [9,10,14,15,52]. The cholesterol found in chylomicron remnants can be used for lipoprotein (VLDL) and/or bile acid formation, or stored as cholesteryl esters [15,52]. Endogenous pathway while chylomicrons are responsible for transport of dietary lipids, VLDL, LDL and HDL is mainly involved in the metabolism of endogenously produced lipids [15]. Endogenously synthesized triglycerides and cholesterol (and cholesteryl esters). Lipoprotein species VLDL: Very Low-Density Lipoproteins, LDL: Low-Density Lipoproteins, HDL: High Density Lipoproteins. Classification and properties of major human plasma lipoproteins. Lipoproteins Major metabolic function chylomicrons structural, IDL: Intermediate Density Lipoproteins, LDL: Low- Density Lipoproteins, Lp (a): lipoprotein abide with phospholipids to form VLDL [9,10,14,15]. After VLDL molecules reach the vasculature Figure 1: The lipid metabolism can be divided into two basic pathways: the exogenous pathway and endogenous pathway. [9,10,14,52]. VLDL activates lipoprotein lipase located in the capillary

Citation: Karam I, Yang YJ and Li JY. Hyperlipidemia Background and Progress. SM J Cardiolog and Cardiovasc Disord. 2017; 3(2): 1011s2. Page 4/8 SMGr up Copyright  Karam I of lipids, which includes both triglycerides and cholesterol, and which amylase, lipase, electrolytes, protein, albumin, and glucose [61], in are formed during the digestion of fats from food. dogs compared to humans [5]. Persistent fasting hyperlipidemia is always considered abnormal and can be either secondary to other Normally, the absorption of chylomicrons increases serum diseases or drug administration or primary. triglycerides for 3-10 hours, but some animals will have high cholesterol and high triglyceride levels for more than twelve hours Treatment of Hyperlipidemia after a meal - one of the main indications of hyperlipidemia. Therapeutic strategies for hyperlipidemia treatment depend In Equine Poor feed quality or decrease in feed intake, particularly on reduce blood lipids, there are many chemical drugs that lower during a period of high-energy requirement (e g, pregnancy, systemic cholesterol level in the body; commonly known as lipid-lowering disease), may result in hyperlipidemia syndrome [17]. Hyperlipidemia drugs. Such as , , ezetimibe and nicotinic acid, but most is seen most commonly in ponies, miniature horses, and donkeys, of them are expensive and have undesirable effect [62]. The main aim and less frequently in standard-size adult horses. of treatment in patient with hyperlipidemia is to reduce the risk of A number of studies have shown that the feeding of fat developing ischemic heart disease, cardiovascular and cerebrovascular supplements to ruminant’s raises the cholesterol concentration in disease (Figure 2). However, to fight these problems of hyperlipidemia, the serum but not in the tissues or milk in non-ruminants, including to treat hyperlipidemia in human, extensive interventions have been primates and man, hypercholesterolemia may be increased by dietary performed including diet control, exercise and administration of manipulations such as feeding excessive cholesterol or fats with a high hypolipidaemic drugs [63]. One of the most important strategies in saturated content. The serum cholesterol concentration the prevention and treatment of hyperlipidemia includes delaying fat does not rise uniformly and hyper-responsiveness has been variously digestion and absorption through gastrointestinal mechanisms such attributed to excessive absorption of cholesterol, e.g [57]. In some as the inhibition of pancreatic lipase, pancreatic cholesterol esterase species of monkey, to diminished re-excretion of cholesterol or bile activities as well as the inhibition of cholesterol micellization, and acids, or to the failure of absorbed cholesterol to exert appropriate bile acid binding. However, the complex mechanisms by which these feedback inhibition on cholesterol synthesis. As ruminants normally molecules act are only beginning to be appreciated. Evidences suggest derive all of their cholesterol from endogenous biosynthesis [57], it is that lipid lowering modes of therapy also reduce inflammation, which reasonable to suppose that the fat-induced hypercholesterolemia in may reduce the risk of cardiovascular events; even for individuals ruminants is due to either an increased synthesis of cholesterol and/ with LDL-Clevels in the normal range (< 130 mg/dL) based on the or a decreased fecal excretion of cholesterol or bile acids. National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines. Several drugs are used to decrease LDL A great number of animal models, such pigeons, chickens, swine, cholesterol such as “-statins” (HMG-CoA reductase inhibitor), bile cats, dogs, non-human primates, mice, rabbits and rats, have been acid sequestrates, nicotinic acid and gemfibrozil. tested for hyperlipidemia [58,59]. Consequently, it has been tried to provoke hyperlipidemia in laboratory animals, in order to understand The most important drugs for the treatment of dyslipidemia are better the relationship between disorders in cholesterol metabolism by far, one group of drugs (statins) lowers cholesterol by interfering and atherogenesis and to test possible treatments for the reduction of with the cholesterol biosynthetic pathway. Most of the drugs (statins) circulating cholesterol level. available today are inhibitors of 3-hydroxy3 methyl gluataryl coenzyme -A reductase, which is involved in cholesterol biosynthesis For inducing hypercholesterolemia in rats triglycerides-rich diets in the liver. The most effective and widely used drugs for the treatment containing cholesterol, with or without cholic acid have been used of hyperlipidemia are the “-statins”. Their primary site of action is [60]; the level of cholesterol varies substantially as well. in the liver where they inhibit HMG- CoA reductase; the metabolic Diagnosis 0f Hyperlipidemia pathway that produces cholesterol and isoprenoids. Statins have been Diagnosis of hyperlipidemia it depend on laboratory measures for hyperlipidemia indexes, which include Triglycerides TG, Total Cholesterol TC, Low Density Lipoprotein LDL and High Density Lipoprotein HDL, hyperlipidemia can be characterized by increasing in TG, TC, LDL and decreasing in HDL, any determination of serum lipid concentrations should always follow a fast of at least 12 h. Methods for quantification and characterization of lipids in blood Routine quantitative assessment of total cholesterol and triglyceride concentrations in serum or plasma is usually achieved by use of spectrophotometric or enzymatic methods [61]. Other methods (e.g., lipoprotein electrophoresis, ultracentrifugation) have also been used but have limited use in the routine clinical evaluation of hyperlipidemic dogs [13,61]. Interference with laboratory measurements it is important to note that lipemia can often interfere with the determination of several analytes, depending on the methodology and analyzer used. Analytic the determination of which has been reported to be affected by lipemia (i.e., falsely increased or Figure 2: The lipid lowering drugs acting on hyperlipidemia. Such as: statins, fibrates, ezetimibe, resins and niacin. decreased) include, but are not limited to, bilirubin, liver enzymes,

Citation: Karam I, Yang YJ and Li JY. Hyperlipidemia Background and Progress. SM J Cardiolog and Cardiovasc Disord. 2017; 3(2): 1011s2. Page 5/8 SMGr up Copyright  Karam I shown in multiple clinical trials to reduce cardiovascular events and cardiovascular disease have not been shown to consistently improve mortality. Statins have been shown to effectively lower LDL levels and patient-oriented outcomes. reduce both mortality and morbidity associated with coronary heart On the other hand, fibrates decrease fatty acid and triglyceride disease by 30%. However, as noted Steinberg and colleagues [64]; this levels by stimulating the peroxisomalβ-oxidation pathway. Apart still leaves a significant percent TGe of individuals for whom from these drugs, ezetimibe, which selectively inhibits intestinal therapy will not prevent the occurrence of adverse events. Statins cholesterol absorption, cholestyramine, colestipol, and colesevelam, have the most convincing data for primary prevention, especially for which sequester bile acids, torcetrapib, which inhibits cholesterol higher risk patients. Therefore, risk stratification is essential. Statin ester transfer protein, avasimibe, which inhibits acyl-CoA: cholesterol therapy is also recommended for secondary prevention in all patients acyltransferase, implitapide, which inhibits microsomal triglyceride with known cardiovascular disease or the risk equivalent. High-dose transfer protein, and niacin, which modifies lipoproteins, providing statins should be initiated in patients with acute coronary syndrome clinicians with several therapeutic options for lipid lowering. To retard [65]. or prevent the formation of atherosclerosis come Pharmacologic treatment of hyperlipidemia in conjunction with on one of the present therapeutic challenges. Elevated plasma therapeutic lifestyle changes for human can be used for both primary cholesterol levels have long been established as risk factors for CHD, and secondary prevention of cardiovascular disease. There is good and lowering cholesterol levels, particularly low – density lipoprotein evidence for using statins in the secondary prevention of stroke and cholesterol (LDL-C) has been the focus of the prevention of CHD and peripheral arterial disease [66]. it’s squealed for almost 25 years. Hyperlipidemia is a common cause for CVD, with elevated Low- The pharmacological, dietary and herbal treatment of Coronary Density Lipoprotein (LDL) cholesterol levels. National Institute Heart Disease (CHD) is based on the hypothesis that reduced for Health and Clinical Excellence (NICE) guidelines recommend cholesterol biosynthesis will lead to lower blood levels of cholesterol. offering a fixed-dose statin based on CHD risk stratification, and Lowering lipids and cholesterol levels by a drug or dietary recommend against checking cholesterol levels after a patient starts interventions could reduce the risk of Coronary Heart Disease. statin therapy. For secondary prevention, NICE recommends a treat- Current interest in natural products has stimulated the search for to-target therapy that is less aggressive than that recommended by new cholesterol-lowering agents from these sources. Several synthetic the Adult Treatment Panel (ATP) III. The ATP III recommendations hypocholesteromic agents such as statins, fibrates, resins and nicotinic are based on the assumption that achieving the mean LDL cholesterol acid are capable of efficiently reducing plasma Total Cholesterol level observed in clinical trials will produce similar results in practice, (TC) levels, but LDL does not undergo any significant alteration. but no clinical trial has assessed a treat to target strategy. However, Also, synthetic hypolipidemic agents have one or more side effects based on statins medical use, importance, and popularity, Elevated and are unable to increase HDL levels. Karam reported that Aspirin serum lipids have been shown to be a major risk factor for the Eugenol Ester (AEE) which is novel drug compound between aspirin development of coronary heart disease and atherosclerosis [67]. and eugenol had anti-hyperlipidemia effect on blood lipids indexes in rats which induced hyperlipidemia with feeding high fat diet the drug The U.K. National Practice Guidelines U.S., U.K., and Canadian significantly decrease TG, TC, LDL and increase HDL [17]. guidelines are available to help physicians manage hyperlipidemia. These guidelines agree that therapeutic lifestyle changes are the Many herbal medicinal products were reported to have a potential mainstay of hyperlipidemia management, and that LDL cholesterol to reduce lipid and cholesterol in body and to enhance the safety should be the primary target of therapy. Treatment of hyperlipidemia profile by elevating HDL levels and inhibiting lipid oxidation, such improves outcomes for patients with known Coronary Heart Disease as Berberine which had regulation effect on hyperlipidemia indexes (CHD) or the risk equivalent, and for high-risk patients (i.e., those with [69-72]. The major portion of the global population in developing a 10-year CHD risk of greater than 20 percent) without known CHD countries still relies on botanical drugs to meet its health needs [71]. or the risk equivalent. In the past 20 years, major strides have been The attention paid by health authorities to the use of herbal medicines made in the understanding and treatment of hypercholesterolemia has increased considerably, because herbal medicines they are often and other . Since its inception in 1985, the National only medicine available in less developed areas and because they are Cholesterol Education Program (NCEP) in USA has battled to becoming a popular alternative treatment in more developed areas reduce the prevalence of high blood cholesterol through educational [69]. campaigns and science-based practice guidelines, however cholesterol There is an obvious need for more efficacious and alternative levels are still under treated. The U.S. National Cholesterol Education treatment options. Many Chinese herbal medicines contain Program, Adult Treatment Panel (ATP) III guidelines advocate for a polysaccharides which can exert a wide range of pharmacological treat to target approach and are more aggressive than other guidelines effects, including lipid lowering drugs [73]. In modern practice, [68]. there are many drugs which are in use as hypolipidemic agent but the therapy is not cost-effective and as such these drugs do not Omega-3 fatty acids may be a good alternative after myocardial fulfill the WHO guidelines of essential drugs. Herbal treatment of infarction for patients who cannot tolerate statins. Fibrates and hyperlipidemia has no side effects and relatively cheap and locally niacin have not been shown to reduce all-cause mortality in available. secondary prevention, but may be useful adjuncts when statins alone cannot adequately control lipid levels. Other cholesterol- So there are increasing interest in alternative/herbal medicine lowering medications used for primary or secondary prevention of for the prevention and treatment of hypercholesterolemia. Currently

Citation: Karam I, Yang YJ and Li JY. Hyperlipidemia Background and Progress. SM J Cardiolog and Cardiovasc Disord. 2017; 3(2): 1011s2. Page 6/8 SMGr up Copyright  Karam I available hyperlipidemic drugs have been associated with a number of 20. Mcnellis R, Lewis P 3RD. Behavioral Counseling To Promote A Healthful Diet side effects. Many of the medicinal plants widely used to reduce plasma and Physical Activity for Cardiovascular Disease Prevention in Adults With Cardiovascular Risk Factors. Am Fam Physician. 2015;92: 509-10. cholesterol and to reduce the risk of atherosclerosis-related diseases. Therefore it is a need of the day to search other materials from natural 21. Last AR, Ference JD, Falleroni J. Pharmacologic Treatment of Hyperlipidemia. sources that are less toxic, less expensive, which can provide better American Family Physician. 2011; 84: 551. safety and efficacy on a long term usage. Natural products from plants 22. Cameron JL, Capuzzi DM, Zuidema GD, Margolis S. Acute Pancreatitis With area rich source used for centuries to cure various ailments (Figure 2). Hyperlipemia. Evidence For a Persistent Defect In Lipid Metabolism. Am J Med. 1974; 56: 482-487. References 23. Toskes PP. Hyperlipidemic Pancreatitis. Gastroenterol Clin North Am. 1990; 1. Xu QY, Liu yH, Zhang Q, Ma B, Yang ZD, Liu L, et.al. Metabolomic Analysis 19: 783-791. of Simvastatin and Fenofibrate Intervention in High-Lipid Diet-Induced 24. Fortson MR, Freedman SN, Webster PD 3rd. Clinical Assessment Of Hyperlipidemia Rats. Acta Pharmacol Sin. 2014; 35: 1265-1273. Hyperlipidemic Pancreatitis. Am J Gastroenterol. 1995; 90: 2134-2139.

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